Novel substituted N-(1-alkyl-3-hydroxy-4-piperidinyl)benzamides

ABSTRACT

Substituted N-(1-alkyl-3-hydroxy-4-piperidinyl)benzamides, their N-oxide forms, their pharmaceutically acceptable acid addition salts and stereochemically isomeric forms having gastrointestinal motility stimulating properties, compositions containing the same, and methods of treating warm-blooded animals suffering from motility disorders of the gastrointestinal system.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation-in-part of our co-pending application Ser. No.101,115 filed Sept. 25, 1987 now abandoned.

BACKGROUND OF THE INVENTION

In the European Patent No. 76.530 which corresponds to the U.S. Ser. No.403,603 there are described N-(1-alkyl-3-hydroxy-4-piperidinyl)benzamidederivatives which compounds are useful as stimulators of the motility ofgastrointestinal system.

The compounds of the present invention differ therefrom by the fact thatthe piperidinyl moiety is substituted in a previously undisclosed mannerand by their favourable gastrointestinal motility stimulating propertiesand particularly their improved capability to accelerate gastricemptying.

DESCRIPTION OF THE INVENTION

The present invention is concerned with novelN-(4-piperidinyl)-benzamides having the formula ##STR1## the N-oxideforms, the pharmaceutically acceptable acid addition salts andstereochemically isomeric forms thereof, wherein

K¹ is hydrogen, C₁₋₆ alkyl, arylC₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkyloxycarbonyl, aryloxycarbonyl, aminoC₁₋₆ alkyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆ alkyl, aminocarbonyl, mono- or di(C₁₋₆alkyl)aminocarbonyl, pyrrolidinylcarbonyl or piperidinylcarbonyl;

R² is hydrogen or C₁₋₆ alkyl;

R³, R⁴ and R⁵ each independently are hydrogen, C₁₋₆ alkyl, C₁₋₆alkyloxy, halo, hydroxy, cyano, nitro, amino, trifluoromethyl, mono- ordi-(C₁₋₆ alkyl)amino, C₁₋₆ aminocarbonyl, arylcarbonylamino, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylcarbonyloxy,aminosulfonyl, alkylaminosulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, C₁₋₆ alkylthio, mercapto, arylC₁₋₆ alkyloxy or aryloxy;

R⁶ is hydrogen, hydroxy, C₁₋₆ alkyl, C₁₋₆ alkyloxy, halo or amino;

L is a radical of formula ##STR2## wherein Alk is C₁₋₆ alkanediyl orC₃₋₆ alkenediyl;

Y¹ is O, S or NR⁷ ; whereas Y is O, S, NR⁷ or a direct bond; said R⁷being hydrogen or C₁₋₆ alkyl;

R⁸ and R⁹ each independently are hydrogen, C₁₋₆ alkyl, C₁₋₆ alkyloxy,aryl, C₃₋₆ cycloalkyl, arylC₁₋₆ alkyl or (C₃₋₆ cycloalkyl)C₁₋₆ alkyl;provided that R⁸ and R⁹ are other than hydrogen when R⁷ is hydrogen;

R¹⁰ is C₁₋₆ alkyl, C₃₋₆ cycloalkyl, arylC₁₋₆ alkyl, C₁₋₆ alkyloxy or(C₃₋₆ cycloalkyl)C₁₋₆ alkyl;

R¹¹ is aryl, arylC₁₋₆ alkyl, C₁₋₆ alkyloxy or (C₃₋₆ cycloalkyl)C₁₋₆alkyl;

R¹² is C₁₋₆ alkyl, aryl or arylC₁₋₆ alkyl;

R¹³ is C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl, arylC₁₋₆ alkyl or (C₃₋₆cycloalkyl)C₁₋₆ alkyl;

R¹⁴ is arylC₁₋₆ alkyl wherein the C₁₋₆ alkyl moiety is substituted withhydroxy or C₁₋₆ salkylcarbonyloxy;

R¹⁵ and R¹⁶ each independently are hydrogen, C₁₋₆ alkyl, hydroxy, C₁₋₆alkyloxy, amino, mono- or di(C₁₋₆ alkyl)amino, hydroxyC₁₋₆ alkyl, C₁₋₆alkylcarbonyl, C₁₋₆ alkyloxycarbonyl, aminocarbonyl, mono- or di(C₁₋₆alkyl)aminocarbonyl or 2-C₁₋₆ alkyl-1,3-dioxolan-2-yl; or R¹⁵ and R¹⁶combined with the carbon atom bearing said R¹⁵ and R¹⁶ may form acarbonyl or a 1,3-dioxolan-2-ylidene radical;

s is the integer 1,2 or 3;

A is O, S or NR¹⁹ ; said R¹⁹ being hydrogen, C₁₋₆ alkyl, aryl,pyridinyl, pyrimidinyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkyloxycarbonyl orarylC₁₋₆ alkyl;

R¹⁷ and R¹⁸ each independently are hydrogen or C₁₋₆ alkyl, or when A isNR¹⁹ R¹⁷ and R¹⁸ taken together may form a fused benzene residue beingoptionally substituted with halo or C₁₋₆ alkyl;

t is the integer 1 or 2;

R²⁰ is hydrogen or C₁₋₆ alkyl;

B is a bivalent radical of formula --CH₂ --CH₂ --, --C(═O)--CH₂ -- or--CH₂ --CH₂ --CH₂ --, wherein each hydrogen atom independently may bereplaced by C₁₋₆ alkyl substituents, or when R²⁰ is C₁₋₆ alkyl saidbivalent radical may also be 1,2-benzenediyl optionally substituted withhalo or C₁₋₆ alkyl;

E is a bivalent radical of formula --CH₂ --CH₂ --, --CH₂ --N(R²¹)-- or--CH₂ --CH₂ --CH₂ --, wherein each hydrogen atom independently may bereplaced by C₁₋₆ alkyl, or said bivalent radical may also be1,2-benzenediyl optionally substituted with halo or C₁₋₆ alkyl; said R²¹being hydrogen or C₁₋₆ alkyl;

R²², R²³ and R²⁴ each independently are hydrogen or C₁₋₆ alkyl;

n and m are both independently 0 or 1;

G is carbonyl, carboxymethylene, C₁₋₆ alkyloxycarbonylmethylene, C₁₋₆alkylcarbonylmethylene, 5,5-dimethyl-1,3-dioxan-2-ylidene or1,3-dioxolan-2-ylidene; and

aryl is phenyl optionally substituted with 1, 2 or 3 substituents eachindependently selected from halo, hydroxy, C₁₋₆ alkyl, C₁₋₆ alkyloxy,aminosulfonyl, C₁₋₆ alkylcarbonyl, nitro, trifluoromethyl, amino,aminocarbonyl and phenylcarbonyl.

As used in the foregoing definitions the term halo is generic to fluoro,chloro, bromo and iodo; the term C₁₋₆ alkyl is meant to include straightand branch chained saturated hydrocarbon radicals having from 1 to 6carbon atoms such as, for example, methyl, ethyl, 1-methylethyl,1,1-dimethylethyl, propyl, 2-methylpropyl, butyl, pentyl, hexyl and thelike; the term C₁₋₆ cycloalkyl is generic to cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl; the term C₁₋₆ alkanediyl is meant to includebivalent straight or branch chained alkanediyl radicals having from 1 to6 carbon atoms such as, for example, methylene, 1,2-ethanediyl,1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, hexanediyl and thebranched isomers thereof; the term C₃₋₆ alkenediyl is meant to includebivalent straight or branch chained alkenediyl radicals having from 3 to6 carbon atoms.

Said N-oxides of the compounds of formula (I) are meant to comprisethose compounds of formula (I) wherein one or several nitrogen atoms areoxidated to the so called N-oxide, particularly those N-oxides whereinthe piperidine-nitrogen is N-oxidated.

Said acid addition salts as mentioned hereinbefore are meant to comprisethe therapeutically active non-toxic acid addition salt forms which thecompounds of formula (I) are able to form. The latter can convenientlybe obtained by treating the base form with appropriate acids such as,for example, inorganic acids, such as hydrohalic acid, e.g.hydrochloric, hydrobromic and the like, and sulfuric acid, nitric acid,phosphoric acid and the like; or organic acids, such as, for example,acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic,ethanedioic, propanedioic, butanedioic, 2,3-dihydroxybutanedioic,2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic,benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic,2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.Conversely the salt form can be converted by treatment with alkali intothe free base form.

The term acid addition salt also comprises the hydrates and solventaddition forms which the compounds of formula (I) are able to form.Examples of such forms are e.g. hydrates, alcoholates and the like. Saidsolvates are meant to be included within the scope of the presentinvention.

The compounds of formula (I) have at least two asymmetric carbon atomsin their structure, namely those located in the 3- and the 4-position ofthe piperidine nucleus, and consequently, the substituents in the said3- and 4- positions of the piperidine nucleus have either a trans or acis configuration. (S. Cahn, C. Ingold and V. Prelog in Angew. Chem.,Int. Ed. Engl., 5, 385-511 (1966).

Preferred compounds within the invention are those compounds of formula(I) wherein R¹ is hydrogen, C₁₋₆ alkyl, aryloxycarbonyl, mono- ordi(C₁₋₆ alkyl)aminocarbonyl, pyrrolidinylcarbonyl orpiperidinylcarbonyl; and/or R² is hydrogen; and/or R³, R⁴ and R⁵ eachindependently are hydrogen, halo, C₁₋₆ alkyloxy, amino, mono- or di(C₁₋₆alkyl)amino, C₁₋₆ alkylcarbonylamino, nitro, aminosulfonyl, C₁₋₆alkylaminosulfonyl or C₁₋₆ alkylsulfonyl.

Particularly preferred compounds within the invention are thosepreferred compounds of formula (I) wherein the substituents on the 3-and the 4-position of the piperidine ring have the cis configuration.

More particularly preferred compounds within the invention are thosecompounds of formula (I) wherein aryl is phenyl optionally substitutedwith 1, 2 or 3 substituents each independently selected from halo,hydroxy, C₁₋₆ alkyl and C₁₋₆ alkyloxy; Alk is a C₁₋₄ alkanediyl radical;and L is a radical of formula

(a) wherein Y¹ is NR⁷, said R¹ being hydrogen or C₁₋₄ alkyl, and R⁸ andR⁹ are both C₁₋₄ alkyl; or

(b) wherein R¹⁰ is C₁₋₄ alkyl and R¹¹ is aryl or C₁₋₄ alkyloxy; or

(c) wherein Y¹ is NR⁷, said R⁷ being hydrogen or C₁₋₄ alkyl and R¹² isC₁₋₄ alkyl; or

(d) wherein R¹³ is C₁₋₄ alkyl, C₃₋₆ cycloalkyl or aryl; or

(e) wherein Y¹ is NR⁷, said R⁷ being hydrogen or C₁₋₄ alkyl; or

(f) wherein Y is O, NR⁷ or a direct bond, R¹⁵ is hydrogen, C₁₋₄ alkyl,hydroxy, C₁₋₄ alkyloxy, amino, mono- or di(C₁₋₄ alkyl)amino, hydroxyC₁₋₄alkyl, C₁₋₄ alkylcarbonyl, C₁₋₄ alkyloxycarbonyl or aminocarbonyl andR¹⁶ is hydrogen or C₁₋₄ alkyl, or R¹⁵ and R¹⁶ combined with the carbonatom bearing said R¹⁵ and R¹⁶ may form a carbonyl or a1,3-dioxolan-2-ylidene radical; or

(g) wherein Y is O, NR; or a direct bond and A is O or NR¹⁹, said R¹⁹being hydrogen, C₁₋₄ alkyl, aryl, pyridinyl, pyrimidinyl, C₁₋₄alkylcarbonyl, C₁₋₄ alkyloxycarbonyl or arylC₁₋₄ alkyl; or

(h) wherein B is 1,2-ethanediyl or when R²⁰ is C₁₋₄ alkyl B may also be1,2-benzenediyl optionally substituted with halo or C₁₋₄ alkyl; or

(i) wherein E is 1,3-propanediyl optionally substituted with C₁₋₄ alkyl,1,2-benzenediyl optionally substituted with halo or C₁₋₄ alkyl, or abivalent radical of formula --CH₂ --N(R²¹)--, said R²¹ being hydrogen orC₁₋₄ alkyl; or

(j) wherein R²³ and R²⁴ are both hydrogen; or L is a radical of formula

(k) wherein G is carbonyl, C₁₋₄ alkyloxycarbonylmethylene, C₁₋₄alkylcarbonylmethylene, 5,5-dimethyl-1,3-dioxan-2-ylidene or1,3-dioxolan-2-ylidene.

Still more particularly preferred compounds within the invention arethose more particularly preferred compounds of formula (I) wherein thebenzamide part is substituted on the meta position with R³ being chloro,bromo, C₁₋₄ alkylaminosulfonyl, aminosulfonyl or C₁₋₄ alkylsulfonyl, onthe para position with R⁴ being amino and on the ortho position with R⁵being hydroxy or C₁₋₄ alkyloxy.

Especially preferred compounds within the invention are those moreparticularly preferred compounds of formula (I) wherein R¹ is hydrogenor methyl and R³, R⁴ and R⁵ respectively are 2-methoxy, 4-amino and5-chloro.

An interesting subgroup of compounds of formula (I) comprises thosecompounds, preferred, particularly preferred, more particularlypreferred and especially preferred compounds wherein L is a radical offormula (a), (d) or (e).

Another interesting subgroup of compounds of formula (I) comprises thosecompounds, preferred, particularly preferred, more particularlypreferred and especially preferred compounds wherein L is a radical offormula (k).

Still another interesting subgroup of compounds of formula (I) comprisesthose compounds, preferred, particularly preferred, more particularlypreferred and especially preferred compounds wherein L is a radical offormula (f), (g), (h) or (i).

In order to simplify the structural representations of the compounds offormula (I) and of certain starting materials and intermediates thereof,the radical ##STR3## will hereafter be represented by the symbol D.

The compounds of formula (I) can be prepared by N-alkylating apiperidine of formula (II) with an intermediate of formula (III).##STR4## W as used in the reaction of (III) with (II) and in thefollowing reaction schemes is an appropriate leaving group such as, forexample, halo, preferably, chloro, bromo or iodo, or a sulfonyloxygroup, e.g. methanesulfonyloxy, 4-methylbenzenesulfonyloxy and the likeleaving groups.

The N-alkylation reaction of (II) with (III) is conveniently conductedin a reaction-inert solvent such as, for example, an aromatichydrocarbon, e.g. benzene, methylbenzene, dimethylbenzene and the like;an alkanol, e.g. methanol, ethanol, 1-butanol and the like; a ketone,e.g. 2-propanone, 4-methyl-2-pentanone and the like; an ether, e.g.1,4-dioxane, 1,1'-oxybisethane, tetrahydrofuran and the like; a polaraprotic solvent, e.g. N,N-dimethylformamide, N,N-dimethylacetamide,dimethyl sulfoxide, hexamethylphosphor triamide, 1,3-dimetyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone,1,3-dimethyl-2imidazolidinone, nitrobenzene, 1-methyl-2-pyrrolidinoneand the like or a mixture of such solvents.

The addition of an appropriate base such as, for example, an alkali oran earth alkaline metal carbonate, hydrogen carbonate, hydroxide,alkoxide or hydride, e.g. sodium carbonate, sodium hydrogen carbonate,potassium carbonate, sodium hydroxide, sodium methoxide, sodium hydrideand the like or an organic base such as, for example an amine e.g.N,N-dimethyl-4-pyridinamine, N,N-diethylethanamine,N-(1-methylethyl)-2-propanamine, 4-ethylmorpholine and the like may beutilized to pick up the acid which is liberated during the course of thereaction. In some instances the addition of a iodide salt, preferably analkali metal iodide, is appropriate. Somewhat elevated temperatures mayenhance the rate of the reaction.

In this and the following preparations, the reaction products may beisolated from the reaction mixture and, if necessary, further purifiedaccording methodologies generally known in the art, such as, forexample, extraction, destillation, crystallization, trituration andchromatography.

The compounds of formula (I) can also be prepared by the amidationreaction of an amine of formula ##STR5## with a carboxylic acid offormula ##STR6## or a functional derivative thereof, such as a halide, asymmetrical or mixed anhydride or an activated ester. Said functionalderivative may be generated in situ, or if desired, be isolated andfurther purified before reacting it with the amine of formula (IV).Functional derivatives may be prepared following art-known procedures,for example, by reacting the carboxylic acid of formula (V) with thionylchloride, phosphorous trichloride, polyphosphoric acid, phosphorylchloride and the like, or by reacting the carboxylic acid of formula (V)with an acyl halide, e.g. acetyl chloride, ethyl carbonochloridate andthe like. Or the intermediates (IV) and (V) may be coupled in thepresence of a suitable reagent capable of forming amides, e.g.dicyclohexylcarbodiimide, 2-chloro-1-methylpyridinium iodide and thelike.

Said amidation reactions may conveniently be carried out by stirring thereactants in a suitable reaction-inert solvent, such as, for example, ahalogenated hydrocarbon, e.g. dichloromethane, trichloromethane and thelike, an aromatic hydrocarbon, e.g. methylbenzene and the like, anether, e.g. 1,1'-oxybisethane, tetrahydrofuran and the like or a dipolaraprotic solvent, e.g. N,N-dimethylformamide, N,N-dimethylacetamide andthe like. The addition of a suitable base may be appropriate, inparticular a tertiary amine such as, N,N-diethylethanamine. The water,the alcohol or the acid which is liberated during the course of thereaction may be removed from the reaction mixture accordingmethodologies generally known in the art such as, for example,azeotropical distillation, complexation and salt formation. In someinstances it may be advantageous to cool the reaction mixture. Furtherit may be expedient to protect amino or hydroxy groups during the courseof the reaction to avoid unwanted side reactions. Suitable protectinggroups comprise readily removeable groups such as C₁₋₆ alkylcarbonyl,C₁₋₆ alkyloxycarbonyl, arylC₁₋₆ alkyl and the like protective groups.

The compounds of formula (I) wherein L is a radical of formula (a), (b),(c), (f) or (g), said compounds being represented by formula (I-a-1),can also be prepared by reacting a piperidine of formula (VI) with analcohol or amine of formula (VII). ##STR7## In the reaction of (VII)with (VI) T¹ -- denotes a radical of formula ##STR8## wherein R⁸, R⁹,R¹⁰, R¹¹, R¹², R¹⁵, R¹⁶, R¹⁷, R¹⁸, s and t have the above describedmeanings and Y² denotes O, S, NR¹ or a direct bond whichever isallowable under the definition of L.

The compounds of formula (I) wherein L is a radical of formula (a), (c),(d) or (e) and those compounds of formula (I) wherein L is a radical offormula (f) of (g) wherein Y is other than a direct bond, said compoundsbeing represented by (I-a-2), can also be prepared by reacting analcohol, thiol or amine of formula (VIII) with a reagent of formula(IX). ##STR9## In the reaction of (IX) with (VIII) T² -- denotes aradical of formula ##STR10## wherein R⁸, R⁹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷, R¹⁸, s and t have the above described meanings and Y³ denotes O, Sor NR; whichever is allowable under the definition of L.

The reactions of (VII) with (VI) and (VIII) with (IX) are convenientlyconducted in a suitable reaction-inert solvent, such as, for example, ahydrocarbon, e.g. benzene, a ketone, e.g., acetone, a halogenatedhydrocarbon, e.g. dichloromethane, trichloromethane, an ether, e.g.1,1'-oxybisethane, tetrahydrofuran and the like. An appropriate basesuch as, for example, an alkali metal carbonate, sodium hydride or anorganic base such as, for example, N,N-diethylethanamine or N-(1-methylethyl)-2-propnamine may be utilized to pick up the acid which isliberated during the course of the reaction. Somewhat elevatedtemperatures may enhance the rate of the reaction.

The compounds of formula (I) wherein L is a radical of formula (a), (c),(f) or (g), wherein Y¹ or Y are NH, said compounds being represented by(I-a-3), can be prepared by reacting an isocyanate of formula (X) withan alcohol or amine of formula (XI). ##STR11## In (I-a-3) and (XI) T³ --denotes a radical of formula ##STR12## wherein R⁸, R⁹, R¹², R¹⁵, R¹⁶,R¹⁷, R¹⁸, s and t have the above described meanings.

The compounds of formula (I) wherein L is a radical of formula (a)wherein R⁸ is hydrogen, said compounds being represented by (I-a-4) canbe prepared by reacting an isocyanate of formula (XII) with an alcohol,thiol or amine of formula (VIII). ##STR13## The reaction of (XI) with(X), or (XII) with (VIII) is generally conducted in a suitablereaction-inert solvent such as, for example, an ether, e.g.,tetrahydrofuran and the like. Elevated temperatures may be suitable toenhance the rate of the reaction.

The compounds of formula (I) wherein L is a radical of formula (d) or(e), said compounds being represented by formula (I-a-5), may also beprepared by reacting a carboxylic acid of formula (XIII) or a functionalderivative thereof with an amine, alcohol or thiol of formula (VIII).##STR14## In (I-a-5) and (XIII) T⁴ -- denotes a radical of formula R¹³-- or R¹⁴ -- both having the same meanings as described hereinbefore.

The reaction of (XIII) with (VIII) may generally be conducted followingart-known esterification- or amidation reaction-procedures. For example,the carboxylic acid may be converted into a reactive derivative, e.g. ananhydride or a carboxylic acid halide, which subsequently, is reactedwith (VIII); or by reacting (XIII) and (VIII) with a suitable reagentcapable of forming amides or esters, e.g. dicyclohexyl carbodiimide,2-chloro-1-methylpyridinium iodide and the like. Said reactions are mostconveniently conducted in a suitable solvent such as, for example, anether, e.g. tetrahydrofuran, a halogenated hydrocarbon, e.g.dichloromethane, trichloromethane or a dipolar aprotic solvent, e.g.N,N-dimethylformamide. The addition of a base such as, for example,N,N-diethylethanamine may be appropriate.

The compounds of formula (I) wherein L is a radical of formula (h) or(i), said compounds being represented by formula (I-a-6), can beprepared by N-alkylating an amine of formula (XV) with a piperidinederivative of formula (XIV). ##STR15## In (I-a-6) and (XV) Ts- denotes aradical of formula ##STR16## wherein R²⁰, B and E have the same meaningsas described hereinbefore.

Said N-alkylation reaction is generally carried out following theprocedures described hereinabove for the preparation of (I) startingfrom (II) and (III).

Compounds of formula (I) wherein L is a radical of formula (i), saidcompounds being represented by formula (I-a-7) may also be prepared byreacting an appropriate anhydride of formula (XVI) with an amine offormula (XVII). ##STR17## Said amidation reaction is generally carriedout following the procedures described hereinabove for the preparationof (I) starting from (IV) and (V).

The compounds of formula (I) wherein L is a radical of formula (j) saidcompounds being represented by formula (I-a-8) may be prepared by anumber of cyclization reactions known in the art for preparing hydantoinsystems. For example, the compounds of formula (I-a-8) wherein R²³ andR²⁴ are both hydrogen, said compounds being represented by the formula(I-a-8-a), can be prepared by the cyclization reaction of an aldehyde orketone of formula (XVIII) in the presence of potassium cyanide andammonium carbonate. ##STR18## The compounds of formula (I) canalternatively be prepared by the reductive N-alkylation reaction of anappropriate ketone or aldehyde of formula L'═O (XIX), said L'═O being acompound of formula L--H wherein two geminal hydrogen atoms in said C₁₋₆alkanediyl or C₃₋₆ cycloalkanediyl are replaced by ═O, with a piperidineof formula H--D (II). ##STR19## Said reductive N-alkylation reaction mayconveniently be carried out by catalytically hydrogenating a mixture ofthe reactants in a suitable reaction-inert organic solvent according toart-known catalytic hydrogenating procedures. Suitable solvents are, forexample, water; alkanols, e.g. methanol, ethanol, 2-propanol; cyclicethers, e.g. 1,4-dioxane; halogenated hydrocarbons, e.g. trichloroLmethane; a dipolar aprotic solvent, e.g., N,N-dimethylformamide,dimethyl sulfoxide; or a mixture of such solvents. The term "art-knowncatalytic hydrogenating procedures" means that the reaction is carriedout under hydrogen atmosphere in the presence of an appropriate catalystsuch as, for example, palladium-on-charcoal, platinum-on-charcoal andthe like. In order to prevent the undesired further hydrogenation ofcertain functional groups in the reactants and the reaction products itmay be advantageous to add an appropriate catalyst-poison to thereaction mixture, e.g. thiophene and the like.

The compounds of formula (I) wherein R¹ is hydrogen and wherein thesubstituents in the 3- and 4-position of the piperidine ring have thetrans configuration, said compounds being represented by the formula(I-b-1), may also be prepared by reacting a7-oxa-3-azabicyclo[4.1.0]heptane of formula (XX) with an amide offormula (XXI). The compounds of formula (I-b-1) can further beQ-alkylated or Q-acylated following art-known procedures thus preparingthe corresponding compounds of formula (I-b-2) wherein the substituentsin the 3- and 4-position of the piperidine ring have the transconfiguration and wherein R¹ is other than hydrogen, said R¹ beingrepresented by R^(1-a). ##STR20## In (I-b-1) and (I-b-2) the symbol "t"indicates that the substituents in the 3- and 4- position of thepiperidine ring are in trans configuration.

The reaction of (XX) with (XXI) may be conducted by stirring and, ifdesired, heating the reactants in a suitable reaction-inert solvent,such as, for example, an alcohol, e.g. methanol, ethanol and the like.

The Q-alkylation or O-acylation reactions are conveniently conducted inan inert organic solvent such as, for example, an aromatic hydrocarbon,e.g. benzene, methylbenzene, dimethylbenzene, and the like; a ketone,e.g. 2-propanone, 4-methyl-2-pentanone and the like; an ether, e.g.1,4-dioxane, 1,1'-oxybisethane, tetrahydrofuran and the like; or adipolar aprotic solvent e.g. N,N-dimethylformamide,N,N-dimethylacetamide, dimethyl sulfoxide, 1-methyl-2-pyrrolidinone, andthe like. An appropriate base such as, for example, an alkali metalcarbonate, sodium hydride or an organic base such as, for example,N,N-diethylethanamine or N-(1-methylethyl)-2-propanamine may be utilizedto pick up the acid which is liberated during the course of thereaction. Somewhat elevated temperatures may enhance the rate of thereaction.

The compounds of formula (I) wherein the substituents in the 3- and4-position of the piperidine ring have the cis configuration, saidcompounds being represented by the formula (I-c), may also be preparedby the reductive N-alkylation of a piperidone of formula (XXIII) with anamide of formula (XXI). ##STR21## In (I-c) the symbol "c" indicates thatthe substituents in the 3- and 4-position of the piperidine ring are incis configuration. Said reductive N-alkylation reaction may be carriedout by catalytically hydrogenating a mixture of reactants in a suitablereaction-inert solvent according to art-known catalytic hydrogenatingprocedures described hereinabove for preparing (I) from (XIX) and (II).

The compounds of formula (I) can also be converted into each otherfollowing art-known procedures of functional group transformation. Someexamples of such procedures will be cited hereinafter.

The compounds of formula (I) having a nitro substituent may be convertedinto the corresponding amine by stirring and, if desired, heating thestarting nitro-compounds in a hydrogen-containing medium in the presenceof a suitable amount of an appropriate catalyst in the presence of asuitable solvent. Appropriate catalysts are, for example,platinum-on-charcoal, palladium-on-charcoal, Raney-nickel and the likecatalyst. Suitable solvents are, for example relatively polar solventssuch as, methanol, ethanol and the like.

The hydrogen atoms of the amino function(s) of compounds of formula (I)may be substituted following art-known procedures such as, for example,N-alkylation, N-acylation, reductive N-alkylation and the like methods.

(1) Alkylcarbonyl, arylcarbonyl and the like groups may be introduced onthe nitrogen atom by reacting the starting amine with an appropriatecarboxylic acid or a derivative thereof such as, for example, an acidhalide, acid anhydride and the like in a suitable solvent such as, forexample, an aromatic hydrocarbon, e.g. benzene, a dipolar aproticsolvent, e.g. N,N-dimethylformamide or a mixture of such solvents.

(2) Alkyl groups may be introduced by reacting the starting amine withan alkanal or alkanone under a hydrogen atmosphere in the presence of anappropriate catalyst such as, palladium-on-charcoal,platinum-on-charcoal and the like catalysts, in suitable solvent suchas, methanol, ethanol and the like. In order to prevent the undesiredfurther hydrogenation of certain functional groups in the reactants andthe reaction products it may be advantageous to add an appropriatecatalyst-poison to the reaction mixture, e.g. thiophene and the like.

The compounds of formula (I) containing a substituted amine may beconverted into the corresponding compounds of formula (I) wherein saidnitrogen bears a hydrogen following art-known methods for preparing NHgroups. For example, where said nitrogen is substituted with C₁₋₆alkylcarbonyl, by treating the starting material with an aqueous acidicor basic solution optionally in admixture with an organic solvent.

Compounds of formula (I) containing a hydroxy function may beQ-alkylated or Q-acylated according to art-known procedures, e.g. bystirring the former with an appropriate acylating agent, e.g. an acidanhydride or appropriate alkylating agent, if desired, in the presenceof sodium hydride.

The compounds of formula (I) containing an arylmethoxy substituent maybe converted into the corresponding compounds of formula (I) containinga hydroxy function, following art-known catalytic hydrogenolysisprocedures.

Compounds of formula (I) bearing a protective dioxolan ring may bedeacetalized to yield the corresponding oxo compounds. Saiddeacetalization may be conducted following procedures widely known inthe art such as, for example, by reacting the starting materials in anacidic aqueous medium.

The compounds of formula (I) may also be converted to the correspondingN-oxide forms following art-known procedures for converting a trivalentnitrogen to its N-oxide-form. Said N-oxidation reaction may generally becarried out by reacting the starting material of formula (I) with anappropriate organic or inorganic peroxide. Appropriate inorganicperoxides comprise, for example, hydrogen peroxide, an alkali metal orearth alkali metal peroxide, e.g. sodium peroxide, potassium peroxide,barium peroxide and the like; appropriate organic peroxides may compriseperoxy acids such as, for example, benzenecarboperoxoic acid or halosubstituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoicacid and the like, peroxoalkanoic acids, e.g. peroxoacetic acid and thelike, alkylhydroperoxides, e.g. t.butyl hydroperoxide and the like. SaidN-oxidation may be carried out in a suitable solvent such as forexample, water, lower alkanols, e.g. methanol, ethanol, propanol,butanol and the like, hydrocarbons, e.g. benzene, methylbenzene,dimethylbenzene and the like, ketones, e.g. 2-propanone, 2-butanone andthe like, halogenated hydrocarbons, e.g. dichloromethane,trichloromethane and the like, and mixtures of such solvents. In orderto enhance the reaction rate, it may be appropriate to heat the reactionmixture.

Some of the intermediates and starting materials in the foregoingpreparations are known compounds while others are novel. They may beprepared according to art-known methodologies of preparing said known orsimilarly known compounds. Some procedures for preparing suchintermediates will be described hereinafter in more detail.

The intermediates of formula (II) may be derived from an appropriatelysubstituted piperidine of formula (XXIV) by reacting the latter with areagent of formula (V) or a functional derivative thereof, following theamidation procedures described for the preparation of (I) starting from(IV) and (v), and subsequently removing of the protective group P in thethus obtained intermediate (XXV) following art-known procedures, e.g. byhydrolysis in an acidic or an alkaline aqueous medium or by catalytichydrogenation, depending upon the nature of P. ##STR22## In the reactionof (XXIv) with (V) and in the following reaction schemes P represents asuitable protective group which is readily removeable by hydrogenationor hydrolysation. Preferred protective groups may for example be,hydrogenolyzable groups e.g. phenylmethyl and the like, and hydrolyzablegroups e.g. C₁₋₆ alkyloxycarbonyl and the like.

The intermediates of formula (Iv) can be derived from an appropriatelysubstituted piperidine of formula (XXVI) by alkylating the latter withan appropriate reagent, following the alkylation procedures describedfor (I) starting from (II) and (III) and, subsequently removing theprotective group P in the thus obtained intermediate following art-knownprocedures described hereinbefore. ##STR23## The intermediates offormula (XXIv), can easily be converted into the intermediates offormula (XXVI), for example, by introducing a protective group P¹ on theexocyclic amine function and selectively removing the protective groupP² on the endocyclic amine function. ##STR24## P¹ and P² representssuitable protective groups as defined hereinbefore which are readilyintroduced and removed. Suitable protective groups are, for example,hydrogenolyzable groups as P¹ radicals, e.g. a phenylmethyl group andthe like, and hydrolyzable groups as P² radicals, e.g. C₁₋₆alkyloxycarbonyl, a C₁₋₆ alkylcarbonyl and the like. In general, thepiperidines (vIII), (XXIV) and (XXVI) used as starting materials, can beprepared following procedures analogous to those described in DrugDevelopment Research 8, 225-232 (1986) and in the Published Eur. Pat.Appl. No. 0,076,530 which corresponds to U.S. application Ser. No.403,603, which are incorporated herein as reference.

From formula (I) it is evident that the compounds of this invention andsome intermediates have at least two asymmetric carbon atoms in theirstructure.

Pure stereochemically isomeric forms of the compounds of formula (I) maybe obtained by the application of art-known procedures. Diastereoisomersmay be separated by physical separation methods such as selectivecrystallization and chromatographic techniques, e.g., counter currentdistribution, and enantiomers may be separated from each other by theselective crystallization of their diastereomeric salts with opticallyactive acids or their optically activated derivatives.

It is evident that the cis and trans diastereomeric racemates may befurther resolved into their optical isomers, cis(+), cis(-), trans(+)and trans(-) by the application of methodologies known to those skilledin the art.

Pure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically.

The compounds of formula (I) containing an alkene moiety may be presentin a "E" or "Z" form, said E- and Z-notation having the meaningsdescribed in J. Org. Chem., 35, 2849-2868 (1970).

Stereochemically isomeric forms of the compounds of formula (I) arenaturally intended to be embraced within the scope of the invention.

The compounds of formula (I), the N-oxide forms, the pharmaceuticallyacceptable acid addition salts and possible stereoisomeric forms thereofpossess favourable gastrointestinal motility stimulating properties. Inparticularly they show an accelerated gastric emptying. The latterproperty is clearly evidenced by the results obtained in the "Gastricemptying of a liquid meal in rats"-test described hereinafter.

The stimulatory effect of the subject compounds on the motility of thegastrointestinal system may further be evidenced by, for example, the"Amplification of contrations induced by submaximal transmuralstimulation of Guinea pig ileum"-test described in The Journal ofPharmacology and Experimental Therapeutics, 234, 775-783 (1985) and the"Amplification of contrations induced by supramaximal transmuralstimulation of Guinea pig ileum"-test both described hereinafter.

Similar experiments revealed that some compounds of formula (I), theN-oxide forms, the pharmaceutically acceptable acid addition salts andpossible stereoisomeric forms antagonize the gastrointestinal relaxationas induced by several exogenous agonists.

In view of their useful gastrointestinal motility enhancing propertiesthe subject compounds may be formulated into various forms foradministration purposes.

To prepare the pharmaceutical compositions of this invention, aneffective amount of the particular compound, in base or acid additionsalt form, as the active ingredient is combined in intimate admixturewith a pharmaceutically acceptable carrier, which carrier may take awide variety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirably inunitary dosage form suitable, preferably, for administration orally,rectally or by parenteral injection. For example, in preparing thecompositions in oral dosage form, any of the usual pharmaceutical mediamay be employed, such as, for example, water, glycols, oils, alcoholsand the like in the case of oral liquid preparations such assuspensions, syrups, elixirs and solutions; or solid carriers such asstarches, sugars, kaolin, lubricants, binders, disintegrating agents andthe like in the case of powders, pills, capsules and tablets. Because oftheir ease in administration, tablets and capsules represent the mostadvantageous oral dosage unit form, in which case solid pharmaceuticalcarriers are obviously employed. For parenteral compositions, thecarrier will usually comprise sterile water, at least in large part,though other ingredients, for example, to aid solubility, may beincluded. Injectable solutions, for example, may be prepared in whichthe carrier comprises saline solution, glucose solution or a mixture ofsaline and glucose solution. Injectable suspensions may also be preparedin which case appropriate liquid carriers, suspending agents and thelike may be employed. In the compositions suitable for percutaneousadministration, the carrier optionally comprises a penetration enhancingagent and/or a suitable wetting agent, optionally combined with suitableadditives of any nature in minor proportions, which additives do notcause a significant deletorious effect to the skin. Said additives mayfacilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as aspot-on, as an ointment. Acid addition salts of (I) due to theirincreased water solubility over the corresponding base form, areobviously more suitable in the preparation of aqueous compositions.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

In view of their capability to stimulate the motility of thegastrointestinal system and, in particular their capacity to acceleratethe gastric emptying, the subject compounds are useful to normalize orto improve the gastric and intestinal emptying in subjects sufferingfrom a disturbed motility, e.g. a decreased peristalsis, of theoesophagus and/or stomach and/or small and/or large intestine.

In view of the utility of the compounds of the present invention, thereis provided a method of treating warm-blooded animals suffering frommotility disorders of the gastrointestinal system such as, for example,oesophagitis, gastroparesis, flatulent dyspepsia, non-ulcer dyspepsia,pseudo-obstruction, impaired colonic transit and the like disorders.Said method comprises the systemic administration of an effectivegastrointestinal motor-stimulating amount of a compound of formula (I),a N-oxide, a pharmaceutically acceptable acid addition salt or apossible stereoisomeric form thereof, to warm-blooded animals.

Those of skill in the pertinent art could easily determine the effectivemotor-stimulating amount from the test results presented hereinafter.

In general it is contemplated that an effective amount would be from0.001 mg/kg to 10 mg/kg body weight, and more preferably from 0.01 mg/kgto 1 mg/kg body weight.

The following examples are intended to illustrate and not to limit theinvention in all its aspects. Unless otherwise stated all parts thereinare by weight.

EXPERIMENTAL PART A. Preparation of Intermediates Example 1

To a stirred and cooled (ice bath) solution of 71.12 parts ofpyrrolidine in 210 parts of petroleumether were added dropwise 70.5parts of 4-chlorobutanoyl chloride at a temperature below 15° C. Uponcompletion, stirring was continued overnight at room temperature. Waterwas added. The product was extracted with dichloromethane. The extractwas separated, dried, filtered and evaporated. The residue was distilledat 266 Pa bp. 137° C., yielding 45 parts (51%) of1-(4-chloro-1-oxobutyl)pyrrolidine (int. 1).

In a similar manner there were also prepared:

    ______________________________________                                         ##STR25##                                                                    No.  s     R.sup.15      R.sup.16                                                                             R.sup.25                                                                            physical data                           ______________________________________                                        2    2     2-H.sub.3 C   H      H.sub.3 C                                                                           bp. 135° C. at                                                         199.5 Pa                                3    2     2-H.sub.3 C   6-H.sub.3 C                                                                          H     bp. 95° C. at                                                          5.32 Pa                                 4    2     4-H.sub.3 C   H      H     bp. 145° C. at                                                         239.4 Pa                                5    2     2-H.sub.3 C   H      H     bp. 146° C. at                                                         266 Pa                                  6    3     H             H      H     bp. 95° C. at                                                          13.3 Pa                                 7    2     4-H.sub.2 NC(O)                                                                             H      H     --                                      8    2     4-HO          H      H     --                                      9    2     4-C.sub.2 H.sub.5 OC(O)                                                                     H      H     --                                      10   2     3-H.sub.2 NC(O)                                                                             H      H     --                                      11   2     3-HOCH.sub.2  H      H     --                                      12   2     3-HO          H      H     --                                      13   2     H             H      H.sub.3 C                                                                           bp. 129° C. at                                                         199.5 Pa                                14   2     4-(methyl-1,3-                                                                              H      H     bp. 140° C. at                              dioxolan-2-yl)             13.3 Pa                                 15   1     2-C.sub.2 H.sub.5 OC(O)                                                                     H      H     bp. 172° C. at                                                         199.5 Pa                                16   2     4-N(CH.sub.3).sub.2                                                                         H      H     .HCl                                    17   2     3-N(CH.sub.3).sub.2                                                                         H      H     --                                      ______________________________________                                         ##STR26##                                                                                                            physical                              No.  A            R.sup.17                                                                             R.sup.18                                             Alk-W                                                                              data                                                                     ______________________________________                                        18                                                                                  ##STR27##   H      H    (CH.sub.2).sub.3Cl                                                                      .HCl                                  19                                                                                  ##STR28##   H      H    (CH.sub.2).sub.3Cl                                                                      .HCl                                  20                                                                                  ##STR29##   H      H    (CH.sub.2).sub.5Br                                                                      .HCl                                  21                                                                                  ##STR30##   H      H    (CH.sub.2).sub.3Cl                                                                      .HCl                                  22                                                                                  ##STR31##   H      H    (CH.sub.2).sub.3Cl                                                                      .HCl                                  23                                                                                  ##STR32##                                                                                  ##STR33##                                                                              (CH.sub.2).sub.3Cl                                ______________________________________                                    

and 8-(4-chloro-1oxobutyl)-1,4-dioxa-8-azaspiro[4.5]decane; b.p. 120° C.at 5.32 Pa (int. 24).

EXAMPLE 2

(a) To a stirred mixture of 20 parts of2-methyl-4-(phenylmethyl)piperazine, 11.13 parts of sodium carbonate and120 parts of 2propanone were added dropwise 16.28 parts of4-chloro-2-methylbutanoyl chloride. Upon completion, stirring wascontinued for 45 minutes. The precipitated product was filtered off andtaken up in dichloromethane. Water and sodium carbonate were added. Theorganic layer was separated, dried, filtered and evaporated. The residuewas converted into the hydrochloride salt in 2-propanol. The salt wasfiltered off and dried in vacuo at 40° C., yielding 16.5 parts (45.5%)of 1-(4- chloro-2-methyl-1-oxobutyl)-2-methyl-4-(phenylmethyl)piperazinemonohydrochloride (int. 25).

(b) A mixture of 16 parts of1-(4-chloro-2-methyl-1-oxobutyl)-2-methyl-4-(phenylmethyl)piperazinemonohydrochloride, 200 parts of methanol and 7 parts of a formaldehydesolution 40% was hydrogenated at normal pressure and at 60° C. with 2parts of palladium-on-charcoal catalyst 10%. After the calculated amountof hydrogen was taken up, the catalyst was filtered off and the filtratewas evaporated. The residue was purified by column chromatography oversilica gel using a mixture of trichloromethane and methanol, saturatedwith ammonia, (98:2 by volume) as eluent. The pure fractions werecollected and the eluent was evaporated. The residue was converted intothe hydrochloride salt in 2-propanol and 2,2'-oxybispropane, yielding 9parts (72.6%) of 1(-4-chloro-2-methyl-1-oxobutyl)-2,4-dimethylpiperazinemonohydrochloride (int. 26).

Example 3

(a) A mixture of 24.2 parts of 3-methoxy-1-(phenylmethyl)-4piperidinone,16 parts of N-methylmethanamine, 1 part of a thiophene solution inmethanol and 520 parts of methanol was hydrogenated at normal pressureand at 50° C. with 3 parts of palladium-on-charcoal catalyst 10%. Afterthe calculated amount of hydrogen was taken up, the catalyst wasfiltered off and the filtrate was evaporated, yielding 27.3 parts (100%)of cis-3-methoxy-N,N-dimethyl-1-(phenylmethyl)-4-piperidinamine (int.27).

(b) A mixture ofcis-3-methoxy-N,N-dimethyl-1-(phenylmethyl)-4-piperidinamine washydrogenated at normal pressure and at room temperature with 5 parts ofpalladium-on-charcoal catalyst 10%. After the calculated amount ofhydrogen was taken up, the catalyst was filtered off and the filtratewas evaporated, yielding 17 parts (100%) ofcis-3-methoxy-N,N-dimethyl-4-piperidinamine (int. 28).

(c) To a stirred and cooled (ice/bath) mixture of 7.9 parts ofcis-3-methoxy-N,N-dimethyl-4-piperidinamine, 7 parts ofN,N-diethylethanamine, 195 parts of dichloromethane were added dropwise6.16 parts of 4-chlorobutanoyl chloride (temperature <5° C.). Uponcompletion, stirring was continued for 30 minutes. The organic layer waswashed twice with a saturated sodium chloride solution, dried, filteredand evaporated. The residue was purified by column chromatography oversilica gel using a mixture of trichloromethane and methanol (90:10 byvolume) as eluent. The pure fractions were collected and the eluent wasevaporated, yielding 13.7 parts (100%) of cis-1-(4-chloro-1-oxobutyl)-3-methoxy-N,N-dimethyl-4-piperidinamine (int. 29).

Example 4

(a) To a stirred solution of 7.5 parts of 2-(methylamino)ethanol in 75parts of trichloromethane were added 9.8 parts of N,N-diethylethanaminewhile cooling in an ice bath. A solution of 13.4 parts of1pyrrolidinecarbonyl chloride in 52.5 parts of trichloromethane wasadded dropwise (exothermic reaction, the temperature rose from -10° C.to ˜0° C.). Upon complete addition, stirring was continued for 6 hoursat room temperature. Another portion of 1.5 parts of2-(methylamino)ethanol was added and stirring was continued over weekendat room temperature. The separated organic layer was washed with ahydrochloric acid solution 5% and water, dried, filtered and evaporated,yielding 7 parts (40.1%) ofN-(2-hydroxyethyl)-N-methyl-1-pyrrolidinecarboxamide as a residue (int.30).

(b) To a stirred solution of 4 parts ofN-(2-hydroxyethyl)-N-methyl-1pyrrolidinecarboxamide in 22.5 parts ofmethylbenzene were added 2.9 parts of thionyl chloride. After theaddition of a few drops of N,N-dimethylformamide, the reaction mixturewas heated slowly to reflux temperature. After stirring for 2 hours atthis temperature, the mixture was cooled and the whole was evaporated,yielding 4.5 parts (100%) ofN-(2-chloroethyl)-N-methyl-1-pyrrolidinecarboxamide as a residue (int.31).

In a similar manner there was also prepared: (2-chloroethyl)1-pyrrolidinecarboxylate as a residue (int. 32).

Example 5

To a stirred solution of 25 parts of 3-methyl-2,4-imidazolidinedione in198 parts of N,N-dimethylformamide were added portionwise 1.6 parts of asodium hydride dispersion 50% under nitrogen atmosphere (exothermicreaction, cooling). Upon complete addition, stirring was continued for 1hour at room temperature. 45.5 Parts of 1,2-dibromoethane were addeddropwise. Upon completion, the whole was stirred for 2 days at roomtemperature. The reaction mixture was evaporated and the residue wastaken up in a mixture of water and dichloromethane. The separatedorganic layer was dried, filtered and evaporated. The residue waspurified by column chromatography over silica gel using a mixture oftrichloromethane and methanol (95:5 by volume) as eluent. The purefractions were collected and the eluent was evaporated, yielding 35.8parts (73.6%) of 3-(2-bromoethyl)-1-methyl-2,4-imidazolidinedione as aresidue (int. 33).

In a similar manner there were also prepared:

1-(3-chloropropyl)-2-imidazolidinone as a residue (int. 34);

1-(4-chlorobutyl)-3-ethyl-1,3-dihydro-2N-benzimidazol-2-one (int. 35);and

1-(4-chlorobutyl)-3-ethyl-2-imidazolidinone as a residue (int. 36).

Example 6

(a) A solution of 109 parts of bis(1,1-dimethylethyl) dicarbonate in 375parts of trichloromethane was added dropwise to a solution of 40 partsof 4-(methylamino)-1-butanol in 750 parts of trichloromethane (slightlyexothermic reaction). The reaction mixture was evaporated and theresidue was distilled at 26.60 Pa, yielding 50 parts (57.2%) of(1,1-dimethylethyl) (4-hydroxybutyl)methylcarbamate (int. 37).

(b) A solution of 50 parts of (1,1-dimethylethyl)(4-hydroxybutyl)methylcarbamate in 91 parts of dichloromethane was addeddropwise to a mixture of 150 parts of pyridinium dichromate, 112 partsof molecular sieves and 1300 parts of dichloromethane at a temperatureabout 10° C. Upon completion, stirring was continued for 3 hours at roomtemperature. The reaction mixture was filtered, washed with1,1'-oxybisethane and the filtrate was evaporated. The residue waspurified by column chromatography over silica gel using dichloromethaneas eluent. The pure fractions were collected and the eluent wasevaporated with methylbenzene, yielding 35 parts (70%) of(1,1-dimethylethyl) methyl(4-oxobutyl)carbamate as a residue (int. 38).

In a similar manner there were also prepared:

(1,1-dimethylethyl) methyl(3-oxopropyl)carbamate as a residue (int. 39);and

(1,1-dimethylethyl) methyl(2-oxoethyl)carbamate as a residue (int. 40).

Example 7

Gaseous carbonic dichloride was bubbled during 3 hours through asolution of 83 parts of 2-amino-3,4,5-trimethoxybenzoic acid in 63 partsof concentrated hydrochloric acid and 525 parts of water (thetemperature rose to 40° C.). The precipitated product was filtered off,washed with water and dried in vacuo, yielding 60.5 parts (75%) of6,7,8-trimethoxy-2H-3,1-benzoxazine-2,4(1H)-dione; mp. 247.3° C.(int.41).

Example 8

(a) A mixture of 43.9 parts of 1-(4-chloro-1-oxobutyl)pyrrolidine, 55.1parts of cis-3-methoxy-N-(phenylmethyl)-4-piperidinamine, 37.8 parts ofN,N-diethylethanamine and 900 parts of N,N-dimethylformamide was stirredovernight at 70° C. Another portion of 4.4 parts of1-(4-chloro-1-oxobutyl)pyrrolidine was added and stirring was continuedovernight at 70° C. The reaction mixture was evaporated and the residuewas taken up in a mixture of water and sodium carbonate. The product wasextracted with dichloromethane. The extract was washed with water,dried, filtered and evaporated. The residue was purified by columnchromatography over silica gel using a mixture of trichloromethane andmethanol, saturated with ammonia, (95:5 by volume) as eluent. The purefractions were collected and the eluent was evaporated, yielding 53.1parts (59.0%) of cis-1-[4-[3-methoxy-4-[(phenylmethyl)amino]-1piperidinyl]-1-oxobutyl]pyrrolidine as a residue (int. 42).

(b) A mixture of 53 parts ofcis-1-[4-[3-methoxy-4-[(phenylmethyl)amino]-1-piperidinyl]-1-oxobutyl]pyrrolidineand 200 parts of methanol was hydrogenated at normal pressure and atroom temperature with 3 parts of palladium-on-charcoal catalyst 10%.After the calculated amount of hydrogen was taken up, the catalyst wasfiltered off and the filtrate was evaporated. The residue was purifiedby column chromatography over silica gel using a mixture oftrichloromethane and methanol, saturated with ammonia, (95:5 by volume)as eluent. The pure fractions were collected and the eluent wasevaporated, yielding 28.3 parts (71.4%) ofcis-1-[4-(4-amino-3-methoxy-1-piperidinyl)-1-oxobutyl]pyrrolidine as aresidue (int. 43).

In a similar manner there were also prepared:

cis-N-[2-(4-amino-3-hydroxy-1-piperidinyl)ethyl]-N-methyl-1-pyrrolidinecarboxamideas a residue (int. 44).

cis-1-[2-(4-amino-3-methoxy-1-piperidinyl)ethyl]-3-ethyl-2-imidazolidinoneas a residue (int. 45).

Example 9

(a) A mixture of 183.4 parts of ethylcis-3-methoxy-4-[(phenylmethyl)amino]-1-piperidinecarboxylate, 144 partsof (chloromethyl)benzene, 85 parts of sodium carbonate and 720 parts ofmethylbenzene was stirred for 10 days at reflux temperature. Thereaction mixture was filtered and the filtrate was washed three timeswith 400 parts of water, dried, filtered and evaporated. Petroleumetherwas added. The whole was cooled whereupon the product solidified. It wasfiltered off and crystallized from petroleumether. The product wasfiltered off and dried in vacuo at 40° C., yielding 155 parts (64%) ofethyl cis-4-[bis(phenylmethyl)amino]-3-methoxy-1-piperidinecarboxylate;mp. 95.2° C. (int. 46).

(b) To a stirred mixture of 230 parts of potassium hydroxide and 1600parts of 2-propanol were added 155 parts of ethylcis-4-[bis(phenylmethyl)amino]-3-methoxy-1-piperidinecarboxylate. Thewhole was stirred and refluxed for 7 hours. The reaction mixture wasevaporated. Water was added and the mixture was evaporated till alltraces of 2-propanol were removed. The product was extracted withdichloromethane. The extract was washed twice with a sodium chloridesolution in water, dried, filtered and evaporated. The residue waspurified by column chromatography over silica gel using a mixture oftrichloromethane and methanol, saturated with ammonia, (95:5 by volume)as eluent. The pure fractions were collected and the eluent wasevaporated. The residue was taken up in dichloromethane. The solutionwas washed with a sodium hydroxide solution 5%, dried, filtered andevaporated, yielding 70 parts (55%) ofcis-3-methoxy-N,N-bis(phenylmethyl)-4-piperidinamine as a residue (int.47).

(c) Through a stirred solution of 70 parts of cis-3-methoxy-N,N-bis(phenylmethyl)-4-piperidinamine in 368 parts of ethanol and 460 parts ofwater was bubbled gaseous oxirane for 1.5 hour at room temperature. Thewhole was stirred overnight at room temperature. The product wasfiltered off, washed with a mixture of ethanol and water (50:50 byvolume) and crystallized from acetonitrile. The product was filtered offand dried in vacuo at 40° C., yielding 50 parts (61.3%) ofcis-4-bis(phenylmethyl)amino]-3-methoxy-1-piperidineethanol (int. 48).

(d) To a stirred mixture of 5.32 parts ofcis-4-[bis(phenylmethyl)amino]-3-methoxy-1-piperidineethanol and 96parts of dichloromethane were added 3.63 parts of phenylcarbonochloridate while cooling. The whole was stirred for 35 hours atroom temperature. The reaction mixture was evaporated. The residue wassolidified in 2,2'-oxybispropane. The product was filtered off anddried, yielding 6.4 parts (83.4%) ofcis-[2-[4-[bis(phenylmethyl)amino]-3-methoxy-1-piperidinyl]ethyl]phenylcarbonatemonohydrochloride (int. 49).

(e) To a stirred suspension of 6.4 parts ofcis-[2-[4-[bis(phenylmethyl)amino]-3-methoxy-1-piperidinyl]ethyl]phenylcarbonatemonohydrochloride in 105 parts of 1,1'-oxybisethane were added 200 partsof ammonia. After 48 hours, the 1,1'-oxybisethane layer was treated witha sodium hydroxide solution 5%. The reaction mixture was poured intowater. The product was filtered off and crystallized from acetonitrile.The product was filtered off and dried in vacuo at 50° C., yielding 2.13parts (38.2%) ofcis-[2-[4-[bis(phenylmethyl)amino]-3-methoxy-1-piperidinyl]ethyl]carbamate;mp. 162.2° C. (int. 50).

(f) A mixture of 16.3 parts of cis-[2-[4-bis(phenylmethyl)amino-3-methoxy-1-piperidinyl]ethyl]carbamate and 200 parts of methanol washydrogenated at normal pressure and at 50° C. with 2 parts ofpalladium-on-charcoal catalyst 10%. After the calculated amount ofhydrogen was taken up, the catalyst was filtered off and the filtratewas evaporated, yielding 8.5 parts (95.4%) ofcis-[2-(4-amino-3-methoxy-1piperidinyl)ethyl]carbamate as a residue(int. 51).

Example 10

A mixture of 2.21 parts of 1-(2-chloroethyl)-3-ethyl-2-imidazolidinone,3.13 parts of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-(piperidinyl)benzamide, 1.58 parts of sodium carbonate and 90 parts ofN,N-dimethylformamide was stirred and heated for 48 hours at 70° C. Thereaction mixture was evaporated. Water was added and the product wasextracted twice with dichloromethane. The combined extracts were washedwith water, dried, filtered and evaporated. The residue was purified bycolumn chromatography over silica gel using a mixture oftrichloromethane and methanol, saturated with ammonia, (95:5 by volume)as eluent. The first fraction was collected and the eluent wasevaporated. The residue was crystallized from acetonitrile. The productwas filtered off and dried, yielding 3.08 parts (67.8%) ofcis-4-amino-5-chloro-N-[1-[2-(3-ethyl-2-oxo-1-imidazolidinyl)ethyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide;mp. 152.8° C. (compound 1).

In a similar manner there were also prepared:

    __________________________________________________________________________     ##STR34##                                                                    Comp.                                                                         No. L                    R.sup.1                                                                           base/salt                                                                           mp. (°C.)                           __________________________________________________________________________    2   CH.sub.3N(OCH.sub.3)C(O)(CH.sub.2).sub.3                                                           CH.sub.3                                                                          base  174.8                                           ##STR35##           CH.sub.3                                                                          base  67.1                                       4                                                                                  ##STR36##           CH.sub.3                                                                          base  180.6                                      5                                                                                  ##STR37##           CH.sub.3                                                                          base  128.9                                      6                                                                                  ##STR38##           CH.sub.3                                                                          base  105.6                                      7                                                                                  ##STR39##           CH.sub.3                                                                          HCl.H.sub.2 O                                                                       203.5                                      8                                                                                  ##STR40##           CH.sub.3                                                                          H.sub.2 O                                                                           120.0                                      9                                                                                  ##STR41##           CH.sub.3                                                                          H.sub.2 O                                                                           152.2                                      10                                                                                 ##STR42##           C.sub.2 H.sub.5                                                                   base  176.9                                      11                                                                                 ##STR43##           H   base                                             __________________________________________________________________________

EXAMPLE 11

A mixture of 6.3 parts of 1-(3-chloropropyl)-3-ethyl-2-imidazolidinone,4.76 parts ofcis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide, 2.3parts of sodium carbonate, 0.1 parts of potassium iode and 90 parts ofN,N-dimethylacetamide was stirred over weekend at 70° C. After cooling,the reaction mixture was evaporated. The residue was taken up indichloromethane and water. The organic layer was separated, washed twicewith water, dried, filtered and evaporated. The residue was purified bycolumn chromatography over silica gel using a mixture oftrichloromethane and methanol (96:4 by volume) as eluent. The purefractions were collected and the eluent was evaporated. The residue wascrystallized from acetonitrile and a few drops of water at 0° C. Theproduct was filtered off and dried in vacuo at 40° C., yielding 2.83parts (36.6%) ofcis-4-amino-5-chloro-N-[[1-[3-(3-ethyl-2-oxo-1-imidazolidinyl)propyl]-3-methoxy-4piperidinyl]-2-methoxybenzamide;mp. 112.9° C. (compound 12).

In a similar manner there were also prepared:

cis-4-amino-5-chloro-N-[1-[4-(3-ethyl-2-oxo-1-imidazolidinyl)butyl]-3methoxy-4-piperidinyl]-2-methoxybenzamide;mp. 84.2° C. (compound 13); and

cis-4-amino-5-chloro-N-[3-ethoxy-1-[2-(3-ethyl-2-oxo-1-imidazolidinyl)ethyl]-4-piperidinyl]-2-methoxybenzamide;mp. 161.8° C. (compound 14).

Example 12

To a stirred solution of 3.00 parts of1-(4-chloro-1-oxobutyl)pyrrolidine in 67.5 parts ofN,N-dimethylformamide were added 1.93 parts oftrans-4-amino-5-chloro-N-(3-hydroxy-4-piperidinyl)-2-methoxybenzamideand 1.5 parts of N,N-diethylethanamine and the whole was stirred for 18hours at 70° C. The reaction mixture was evaporated and the residue wastaken up in a sodium carbonate solution in water. The product wasextracted with trichloromethane. The extract was washed with water,dried, filtered and evaporated. The residue was purified by columnchromatography over silica gel using a mixture of trichloromethane andmethanol, saturated with ammonia, (90:10 by volume) as eluent. The purefractions were collected and the eluent was evaporated. The residue wascrystallized from acetonitrile. The product was filtered off and dried,yielding 2.1 parts (47.8%) oftrans-4-amino-5-chloro-N-[3-hydroxy-1-[4-oxo-4-(1-pyrrolidinyl)butyl]-4-piperidinyl]-2-methoxybenzamide;mp. 174.7° C. (compound 15).

In a similar manner there were also prepared:

cis-4-amino-5-chloro-N-[1-[2-(2,5-dioxo-1-imidazolidinyl)ethyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide monohydrate; mp. 220.4° C.(compound 16);

cis-[2-[4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy-1piperidinyl]ethyl]1-pyrrolidinecarboxylate;mp. 170.6° C. (compound 17);

trans-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[4-oxo-4-(1-pyrrolidinyl)butyl]-4-piperidinyl]benzamidemonohydrate; mp. 101.1° C. (compound 18);

cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[2-(3-methyl-2,5-dioxo-1-imidazolidinyl)ethyl]-4-piperidinyl]benzamidemonohydrate; mp. 121.0° C. (compound 19);

cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[4-(4-methyl-1-piperidinyl)-4-oxobutyl]-4-piperidinyl]benzamide;mp. 175.9° C. (compound 20);

cis-4-amino-5-chloro-N-[3-hydroxy-1-[4-oxo-4-(1-pyrrolidinyl)butyl]-4piperidinyl]-2-methoxybenzamideas a residue (compound 21); and

cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[2-(4-methyl-1-piperidinyl)-2-oxoethyl]-4-piperidinyl]benzamidehemihydrate; mp. 140.6° C. (compound 22).

Example 13

A mixture of 2.54 parts of 4-chloro-N-methyl-N-phenylbutanamide, 3.14parts ofcis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide,2.45 parts of N,N-diethylethanamine, 0.1 parts of potassium iodide and90 parts of N,N-dimethylformamide was stirred for 20 hours at 80° C. Thereaction mixture was evaporated. The residue was taken up in water andsodium carbonate. The product was extracted with dichloromethane. Theextract was dried, filtered and evaporated. The residue was purified bycolumn chromatography over silica gel using a mixture oftrichloromethane and methanol (95:5 by volume) as eluent. The purefractions were collected and the eluent was evaporated. The residue wascrystallized from acetonitrile and a small amount of water. The productwas filtered off and dried, yielding 2.05 parts (40.4%) ofcis-4-[4-amino-5-chloro-2-methoxybenzoyl)amino]3-methoxy-N-methyl-N-phenyl-1-piperidinebutanamidemonohydrate; mp. 97.4° C. (compound 23).

    ______________________________________                                         ##STR44##                                                                    Comp.                         base/   mp.                                     No.  L                        salt    (°C.)                            ______________________________________                                        24   CH.sub.3C(O)O(CH.sub.2).sub.2                                                                          base    151.7                                   25                                                                                  ##STR45##               base    200.0                                   26                                                                                  ##STR46##               11/2 H.sub.2 O                                                                        96.8- 100.7                             27   (CH.sub.3).sub.2 CHC(O)O(CH.sub.2).sub.2                                                               base    126.8                                   28                                                                                  ##STR47##               base    103.6                                   29                                                                                  ##STR48##               base    188.2                                   30                                                                                  ##STR49##               base    141.8                                   31                                                                                  ##STR50##               base    151.3                                   32                                                                                  ##STR51##               base    133.7                                   33                                                                                  ##STR52##               base    104.9                                   34                                                                                  ##STR53##               base    164.2                                   35                                                                                  ##STR54##               H.sub.2 O                                                                             114.3                                   36                                                                                  ##STR55##               base    183.7                                   37                                                                                  ##STR56##               base    178.2                                   38                                                                                  ##STR57##               2 HCl 1.5 H.sub.2 O                                                                   191.0                                   39                                                                                  ##STR58##               base    210.8                                   40                                                                                  ##STR59##               base    236.0                                   41                                                                                  ##STR60##               base    159.1                                   42                                                                                  ##STR61##               0.5 H.sub.2 O                                                                         134.3                                   43                                                                                  ##STR62##               1.5 H.sub.2 O                                                                         115.8                                   44                                                                                  ##STR63##               base    141.8                                   ______________________________________                                    

In a similar manner there was also prepared:

cis-4-amino-5-chloro-N-[3-ethoxy-1-[2[-methyl(1-pyrrolidinylcarbonyl)-amino]ethyl]-4-piperadinyl]2-methoxybenzamidehemihydrate; mp. 82.7° C. (compound 45)

In a similar manner there is also prepared:

cis-4-amino-5-chloro-N-[1-[4-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-4-oxobutyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide(compound 46 ).

Example 14

A mixture of 4.5 parts ofcis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide,2.12 parts of sodium carbonate, 0.1 parts of potassium iodide and 120parts of 4-methyl-2-pentanone was stirred and refluxed for 15 minutesusing a water separator. Then there were added 3.92 parts of1-(4-chloro-1-oxobutyl)-2,6-dimethylpiperidine and stirring wascontinued first for 3 hours at reflux and then overnight at roomtemperature. Water was added. The product was filtered off and purifiedby column chromatography over silica gel using a mixture oftrichloromethane and methanol (90:10 by volume) as eluent. The purefractions were collected and the eluent was evaporated. The residue wascrystallized from acetonitrile. The product was filtered off and dried,yielding 5.25 parts (70.7%) ofcis-4-amino-5-chloro-N-[1-[4-(2,6-dimethyl-1-piperidinyl)-4-oxobutyl]3-methoxy-4-piperidinyl]-2-methoxybenzamide;mp. 202.1° C. (compound 47).

In a similar manner there were also prepared:

    __________________________________________________________________________     ##STR64##                                                                    Comp.                                                                         No.   L.sup.1           base/salt                                                                            mp. (°C.)                               __________________________________________________________________________    48    1-pyrrolidinyl    base   202.7                                          49    4-morpholinyl     base   191.9                                          50    1-piperidinyl     base   187.0-187.2                                    51    4-methyl-1-piperidinyl                                                                          base   199.0                                          52    2-methyl-1-piperidinyl                                                                          base   178.6                                          53    hexahydro-1H-azepin-1-yl                                                                        base   176.7                                          54    3-(aminocarbonyl)-1-piperidinyl                                                                 H.sub.2 O                                                                            107.1                                          55    3-(hydroxymethyl)-1-piperidinyl                                                                 base    95.9                                          56    1,4-dioxa-8-azaspiro[4.5]dec-8-yl                                                               base   182.4                                          57    3-hydroxy-1-piperidinyl                                                                         H.sub.2 O                                                                             94.6                                          58    4-(2-methyl-1,3-dioxolan-2-yl)-1-                                                               base   177.7                                                piperidinyl                                                             __________________________________________________________________________

cis-4-amino-5-chloro-N-[3-methoxy-1-[4-oxo-4-(1-piperidinyl)butyl]-4-piperidinyl]2-methoxybenzamide;mp.148.6° C. (compound 59);

cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[3-oxo-3-(1-piperidinyl)propyl]-4-piperidinyl]benzamide;mp. 194.7° C. (compound 60);

cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[3-methyl-4-oxo-4-(1-piperidinyl)butyl)-4-piperidinyl]benzamide;mp. 181.2° C. (compound 61);

cis4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[5-oxo-5-(1-piperidinyl)pentyl]-4-piperidinyl]benzamide;mp. 70.9° C. (compound 62);

(E)-cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[4-oxo-4-(1-piperidinyl)-2-butenyl]-4-piperidinyl]benzamide;mp. 162.8° C. (compound 63);

cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[3-methyl-4-(2-methyl-1-piperidinyl)-4-oxobutyl]-4-piperidinyl]benzamideethanedioate(1:1), hemihydrate; mp. 182.7° C. (compound 64);

cis-4-amino-5-chloro-N-[1-[3-(3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamidemonohydrate; mp. 103.4° C. (compound 65); and

cis-4-amino-5-chloro-N-[1-[4-(3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)butyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamidehemihydrate; mp. 103.4° C. (compound 66).

Example 15

To a stirred solution of 4.04 parts ofcis-1-[4-(4-amino-3-methoxy-1-piperidinyl)-1-oxobutyl]pyrrolidine in 225parts of trichloromethane was added a solution of 4.15 parts of3-chloro-5-ethyl-6-hydroxy-2-methoxybenzoyl chloride intrichloromethane. After stirring for 15 minutes at room temperature, 1.9parts of N,N-diethylethanamine were added and the whole was stirredovernight at room temperature. The reaction mixture was washed withwater, saturated with ammonia and twice with water, dried, filtered andevaporated. The residue was purified by column chromatography oversilica gel using a mixture of trichloromethane and methanol, saturatedwith ammonia (90:10 by volume) as eluent. The pure fractions werecollected and the eluent was evaporated. The residue was crystallizedfrom 2,2'-oxybispropane. The product was filtered off and dried,yielding 5.2 parts (71.9%) ofcis-3-chloro-5-ethyl-6-hydroxy-2-methoxy-N-[3-methoxy-1-[4-oxo-4-(1-pyrrolidinyl)butyl]-4-piperidinyl]benzamide;mp. 90.8° C. (compound 67).

In a similar manner there were also prepared:

cis-3-bromo-2-hydroxy-6-methoxy-N-[3-methoxy-1-[4-oxo-4-(1-pyrrolidinyl)butyl]-4-piperidinyl]benzamide; mp. 134.5° C. (compound68);

cis-3-bromo-5-chloro-2-hydroxy-6-methoxy-N-[3-methoxy-1-[4-oxo-4-(1-pyrrolidinyl)butyl]-4-piperidinyl]benzamide;mp. 127.7° C. (compound 69);

cis-2,5-dichloro-N-[3-methoxy-1-[4-oxo-4-(1-pyrrolidinyl)butyl]-4-piperidinyl]benzamidehemihydrate; mp. 156.2° C. (compound 70);

cis-5-(1,1-dimethylethyl)-2-hydroxy-N-[3-methoxy-1-[4-oxo-4-(1-pyrrolidinyl)butyl]-4-piperidinyl]benzamide;mp. 100.0° C. (compound 71);

andcis-N-[3-methoxy-1-[4-oxo-4-(1-pyrrolidinyl)butyl]-4-piperidinyl]-3-(trifluoromethyl)benzamideethanedioate(1:1); mp. 183.6° C. (compound 72).

Example 16

To a stirred and cooled (<5° C.) suspension of 4.84 parts of5-chloro-2-methoxybenzoic acid in 90 parts of trichloromethane wereadded dropwise first 2.34 parts of N,N-diethylethanamine and then 2.56parts of ethyl carbonochloridate at <5° C. Upon completion, stirring wascontinued for 45 minutes in an ice bath. This solution was added to asolution of 4.35 parts ofcis-[2-(4-amino-3-methoxyo-1-piperidinyl)ethyl]carbamate in 60 parts oftrichloromethane at a temperature below 5° C. The mixture was stirredfor 5 hours at room temperature. The product was filtered off (and setaside) and the filtrate was washed with a sodium carbonate solution inwater. From the organic layer, the precipitated product was filtered offand together with the product, which was set aside (see above),crystallized from acetonitrile. The product was filtered off and driedin vacuo at 40° C., yielding 3.67 parts (43.8%) ofcis-[2-[4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy-1-piperidinyl]ethyl]carbamatemonohydrate; mp. 166.8° C. (compound 73).

In a similar manner there were also prepared:

cis-4amino-2-methoxy-N-[3-methoxy-1-[4-oxo-4-(1-pyrrolidinyl)butyl]-4-piperidinyl]-5-[(methylamino)sulfonyl]benzamidemonohydrate; mp. 217.2° C. (compound 74);

cis-5-chloro-2-methoxy-N-[3-methoxy-1-[4-oxo-4-(1-pyrrolidinyl)butyl]-4-piperidinyl]-4-(methylamino)benzamide;mp. 170.4° C. (compound 75);

cis-4-amino-2-ethoxy-N-[3-methoxy-1-[4-oxo-4-(1-pyrrolidinyl)butyl]-4-piperidinyl]-5-nitrobenzamide;mp. 170.7° C. (compound 76);

cis-N-[-b2-[(4-amino-5-chloro-2-methoxybenzoyl)amino)-3-hydroxy-1-piperidinyl]ethyl]-N-methyl-1-pyrrolidinecarboxamide(compound 77); and

cis-4-amino-N-[1-[2-(3-ethyl-2-oxo-1-imidazolidinyl)ethyl]-3-methoxy-4-piperidinyl]-2-methoxy-5-[(methylamino)sulfonyl]benzamide;mp. 224.4° C. (compound 78).

Example 17

To a stirred solution of 2.69 parts ofcis-1-[4-(4-amino-3-methoxy-1-piperidinyl)-1-oxobutyl]pyrrolidine in 45parts of methylbenzene and 72 parts of N,N-dimethylformamide weresuspended 2.79 parts of6,7,8-trimethoxy-2H-3,1-benzoxazine-2,4(1H)-dione. After stirringovernight at room temperature, the reaction mixture was evaporated. Theresidue was purified by column chromatography over silica gel using amixture of trichloromethane and methanol, saturated with ammonia, (95:5by volume) as eluent. The pure fractions were collected and the eluentwas evaporated. The residue was converted into the hydrochloride salt in2-propanol. The whole was evaporated to dry and the residue wascrystallized from acetonitrile. The product was filtered off and dried,yielding 3.48 parts (72.8%) ofcis-2-amino-3,4,5-trimethoxy-N-[3-methoxy-1-[4-oxo-4-(1-pyrrolidinyl)butyl]-4-piperidinyl]benzamidedihydrochloride.monohydrate; mp. 176.5° C. (compound 79).

Example 18

To a stirred and cooled solution (5° C.) of 3.99 parts ofcis-4-amino-N-[1-(2-aminoethyl)-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamidein 90 parts of trichloromethane were added 1.32 parts ofN,N-diethylethanamine. Then there was added dropwise a solution of 1.18parts of dimethylcarbamic chloride in 60 parts of trichloromethane at atemperature below 5° C. Upon completion, stirring was continued firstfor one hour while cooling in an ice bath and further for 40 hours atroom temperature. The reaction mixture was washed successively withwater, sodium carbonate solution in water, and water, dried, filteredand evaporated. The product was filtered off and crystallized fromacetonitrile, yielding 3.12 parts (73%) ofcis-4-amino-5-chloro-N-[1-[2-[(dimethylamino)carbonylamino]ethyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide;mp. 206.5° C. (compound 80).

In a similar manner there were also prepared:

ethylcis-[2-[4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy-1-piperidinyl]ethyl]carbamate;mp. 164.7° C. (compound 81);

cis-4-amino-5-chloro-N-[1-[2-[(dibutylamino)carbonylamino]ethyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide;mp. 139.5° C. (compound 82);

cis-α-[[2-[4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy-1-piperidinyl]ethyl]aminocarbonyl]benzenemethanolacetate (ester); mp. 100.3° C. (compound 83);

cis-N-[2-[4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy-1-piperidinyl]ethyl]-4-methyl-1-piperazinecarboxamide;mp. 220.5° C. (compound 84);

cis-N-[2-[4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy-1-piperidinyl]ethyl]-N,4-dimethyl-1-piperazinecarboxamide;mp. 135.1° C. (compound 85); and

cis-N-[4-[4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy-1-piperidinyl]butyl]-N-methyl-1-pyrrolidinecarboxamidemonohydrate; mp. 106.7° C. (compound 86)

Example 19

To a stirred suspension of 2.99 parts of α-(hydroxymethyl)benzeneaceticacid in 60 parts of trichloromethane were added dropwise first 1.82parts of N,N-diethylethanamine and then 1.95 parts of ethylcarbonochloridate at a temperature below 5° C. Upon completion, stirringwas continued for 45 minutes at this low temperature. The thus obtainedsolution was added dropwise to a solution of 5.35 parts ofcis-4-amino-N-[1-(2-aminoethyl)-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamidein 45 parts of trichloromethane while the temperature was kept below 10°C. Upon completion, the whole was stirred for 20 hours at roomtemperature. The organic layer was washed with a sodium carbonatesolution in water and with water, dried, filtered and evaporated. Theresidue was purified by column chromatography over silica gel using amixture of trichloromethane and methanol, saturated with ammonia, (98:2by volume) as eluent. The pure fractions were collected and the eluentwas evaporated. The residue was crystallized from acetonitrile and a fewdrops of water. The product was filtered off and dried in vacuo at 30°C., yielding 0.76 parts (10.0%) ofcis-N-[2-[4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy-1-piperidinyl]ethyl]-α-(hydroxymethyl)benzeneacetamide;mp. 114.0° C. (compound 87).

Example 20

A mixture of 1.85 parts of 1,3-isobenzofurandione, 4.4 parts ofcis-4-amino-N-[1-(3-aminopropyl)-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamideand 45 parts of methylbenzene was stirred for 3 hours at refluxtemperature, using a water separator. The reaction mixture wasevaporated. The residue was taken up in trichloromethane. The organicphase was washed with a saturate solution of sodium carbonate and water,dried, filtered and evaporated. The residue was purified by columnchromatography over silica gel using a mixture of trichloromethane andmethanol, saturated with ammonia, (97:3 by volume) as eluent. The purefractions were collected and the eluent was evaporated. The residue wascrystallized from acetonitrile. The product was filtered off and dried,yielding 2.5 parts (42,4%) ofcis-4-amino-5-chloro-N-[1-[3-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide;mp. 208.2° C. (compound 88).

In a similar manner there was also prepared:

cis-4-amino-5-chloro-N-[1-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamidehemihydrate; mp. 113.2° C. (compound 89).

Example 21

To a stirred suspension of 3.97 parts ofcis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-(4-oxopentyl)-4-piperidinyl]benzamidein 19.2 parts of ethanol was added first a solution of 0.72 parts ofpotassium cyanide in 12 parts of water and then 2.88 parts of ammoniumcarbonate. The whole was stirred overnight at about 55° C. Aftercooling, the reaction mixture was poured into water. Ethanol wasevaporated whereupon a precipitate was formed. It was filtered off,washed with water and boiled twice in acetonitrile. The product wasfiltered off and crystallized from 4-methyl-2-pentanone, yielding 1.25parts (26.7%) ofcis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[3-(4-methyl-2,5-dioxo-4-imidazolidinyl)propyl]-4-piperidinyl]benzamide;mp. 235.8° C. (compound 90).

In a similar manner there was also prepared:

cis-4-amino-5-chloro-N-[1-[3-(2,5-dioxo-4-imidazolidinyl)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide;mp. 150.1° C. (compound 91).

Example 22

A mixture of 10 parts of 3,3-dimethyl-1,5-dioxaspiro[5.5]undecan-9-one,9.42 parts ofcis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4piperidinyl)benzamide, 1part of a solution of thiophene in methanol 4% and 200 parts of methanolwas hydrogenated at normal pressure and at room temperature with 2 partsof platinum-on-charcoal catalyst 5%. After the calculated amount ofhydrogen was taken up, the catalyst was filtered off and the filtratewas evaporated. The residue was crystallized from acetonitrile. Theproduct was filtered off and dried in vacuo at 60° C., yielding 9.33parts (62.6%) ofcis-4-amino-5-chloro-N-[1-(3,3-dimethyl-1,5-dioxaspiro[5.5]undec-9-yl)-3-methoxy-4-piperidinyl]-2-methoxybenzamide;mp. 187.5° C. (compound 92).

In a similar manner there were also prepared:

cis-4-amino-5-chloro-N-[1-[(1,4-dioxaspiro[4.5]dec-8-yl)methyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide;mp. 189.4° C. (compound 93);

ethyltrans-4-[4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy-1-piperidinyl]cyclohexanecarboxylate;mp. 153.0° C. (compound 94);

ethylcis-4-[4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy-1-piperidinyl]cyclohexanecarboxylate;mp. 165.9° C. (compound 95);

(±)-[1(cis),3α,4α-N-[1-(4-acetylcyclohexyl)-3-methoxy-4-piperidinyl]-4-amino-5-chloro-2-methoxybenzamide;mp. 205.2° C. (compound 96);

(±)-[1(trans),3α,4α)]-N-[1-(4-acetylcyclohexyl)-3-methoxy-4-piperidinyl]-4-amino-5-chloro-2-methoxybenzamide;mp. 198.0° C. (compound 97);

(1,1-dimethylethyl)cis-[2-[4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy-1-piperidinyl]ethyl]methylcarbamateas a residue (compound 98);

(1,1-dimethylethyl)cis-[3-[4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy-1-piperidinyl]propyl]methylcarbamate;mp. 143.3° C. (compound 99); and

(1,1-dimethylethyl)cis-[4-[4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy-1-piperidinyl]butyl]methylcarbamateas a residue (compound 100).

Example 23

A mixture of 2.8 parts ofcis-α-[[2-[4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy-1-piperidinyl]ethyl]aminocarbonyl]benzenemethanolacetate(ester), 1.1 parts of concentrated hydrochloric acid and 28 partsof methanol was stirred for 20 hours at reflux temperature. The reactionmixture was evaporated. The residue was taken up in water. The solutionwas treated with ammonia. The aqueous phase was extracted withdichloromethane. The organic layer was washed with water, dried,filtered and evaporated. The residue was crystallized from methanol. Theproduct was filtered off and dried in vacuo at 50° C., yielding 0.,67parts (25.7%) ofcis-N-[2-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy-1-piperidinyl]ethyl]-α-hydroxybenzeneacetamide;mp. 227.6° C. (compound 101).

Example 24

To a stirred solution of 2 parts ofcis-4-amino-5-chloro-N-[3-hydroxy-1-[4-oxo-4-(1-pyrrolidinyl)butyl]-4-piperidinyl]-2-methoxybenzamidein 31.5 parts of tetrahydrofuran were added 0.7 parts ofN,N-diethylethanamine. The whole was cooled in an ice bath and asolution of 0.72 parts of phenyl carbonochloridate in 13.5 parts oftetrahydrofuran was added dropwise to the thus obtained solution(slightly exothermic reaction). Upon complete addition, the whole wascarbonochloridate in 9 parts of tetrahydrofuran was added. Afterstirring for 30 minutes in an ice bath, a solution of 0.07 parts ofphenyl carbonochloridate in 9 parts of tetrahydrofuran was added. Thewhole was stirred further for 30 minutes in an ice bath and the reactionmixture was poured into water. The product was extracted withdichloromethane. The extract was dried, filtered and evaporated. Theresidue was crystallized from acetonitrile. After cooling to 0° C., theproduct was filtered off and dried in vacuo at 50° C., yielding 1.3parts (50.5%) ofcis-[4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-4-oxo-4-(1-pyrrolidinyl)butyl]-3-piperidinyl]phenylcarbonate(compound 102).

In a similar manner there were also prepared:

cis-[4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-[2-(3-ethyl-2-oxo-1-imidazolidinyl)ethyl]-3-piperidinyl]phenylcarbonate(compound 103); and

cis-[4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-[2-[methyl(1-pyrrolidinylcarbonyl)amino]ethyl]-3-piperidinyl]phenylcarbonate(compound 104).

Example 25

To a stirred and cooled (ice/bath) solution of 3 parts ofcis-[4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-[2-(3-ethyl-2-oxo-1-imidazolidinyl)ethyl]-3-piperidinyl]phenylcarbonatein 135 parts of tetrahydrofuran was added a solution of 6.4 parts ofpyrrolidine in 27 parts of tetrahydrofuran. Upon completion, stirringwas continued for 1 hour at room temperature. The reaction mixture waspoured into water. The product was extracted with dichloromethane. Theextract was washed with water, dried, filtered and evaporated. Theresidue was boiled in 2,2'-oxybispropane and a few drops ofacetonitrile. The product was filtered off and crystallized fromacetonitrile at 0° C. It was filtered off again and dried in vacuo at50° C., yielding 1.95 parts (66%) ofcis-[4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-[2-(3-ethyl-2-oxo-1-imidazolidinyl)ethyl]-3-piperidinyl]1-pyrrolidinecarboxylate;mp. 214.5° C. (compound 105).

In a similar manner there were also prepared:

cis-[4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-[4-oxo-4-(1-pyrrolidinyl)butyl]-3-piperidinyl]dimethylcarbamate; mp. 214.0° C. (compound 106);

cis-[4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-[2-(3-ethyl-2-oxo-1-imidazolidinyl)ethyl]-3-piperidinol]-dimethylcarbonate;mp. 111.7° C. (compound 107); and

cis-[4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-[2-[methyl(1-pyrrolidinylcarbonyl)amino]ethyl]-3-piperidinyl]dimethylcarbonate monohydrate; mp. 170.1° C. (compound 108).

Example 26

A mixture of 2.1 parts ofcis-4-amino-5-chloro-N-[1-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-4-oxobutyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide,0.74 parts of sulfuric acid and 40 parts of water was stirred for 2hours at reflux temperature. After cooling, the reaction mixture wasmade alkaline with sodium carbonate while cooling. The product wasextracted with trichloromethane. The extract was washed with water,dried, filtered and evaporated. The residue was crystallized fromacetonitrile. The product was filtered off and dried in vacuo at 60° C.,yielding 1 part (51.9%) ofcis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[4-oxo-4-(4-oxo-1-piperidinyl)butyl]-4-piperidinyl]benzamide;mp. 156.9° C. (compound 109).

In a similar manner there were also prepared:

cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-(4-oxocyclohexyl)-4-piperidinyl]benzamide;mp. 209.5° C. (compound 110);

cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[(4-oxocyclohexyl)methyl]-4-piperidinyl]benzamide;mp. 211.6° C. (compound 111); and

cis-N-[1-[4-(4-acetyl-1-piperidinyl)-4-oxobutyl]-3-methoxy-4-piperidinyl]-4-amino-5-chloro-2-methoxybenzamide;mp. 208.5° C. (compound 112).

Example 27

To a stirred and cooled (ice bath) solution of 3.30 parts ofcis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[4-oxo-4-(1-pyrrolidinyl)butyl]-4-piperidinyl]benzamidein 225 parts of trichloromethane were added 1.55 parts of3-chlorobenzenecarboperoxoic acid. The temperature was allowed to reachroom temperature and the whole was stirred overnight. The mixture wasconcentrated. The concentrate was purified by column chromatography oversilica gel using a mixture of trichloromethane and methanol, saturatedwith ammonia, (90:10 by volume) as eluent. The pure fractions werecollected and the eluent was evaporated. The residue was taken up inacetonitrile and the whole was evaporated again. The crystallizedproduct was filtered off and dried, yielding 2.45 parts (69.6%) ofcis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[4-oxo-4-(1-pyrrolidinyl)butyl]-4-piperidinyl]benzamide,N-oxide;mp. 140.0° C. (compound 113).

Example 28

To a stirred solution of 4 parts ofcis-4-amino-5-chloro-2-methoxy-N-3-methoxy-1-[4-oxo-4-(1-pyrrolidinyl)butyl]-4-piperidinyl]benzamidein 20 parts of acetic acid were added 0.89 parts of acetic acidanhydride. Upon complete addition, stirring was continued overnight atroom temperature. The reaction mixture was poured into water and thewhole was treated with ammonium hydroxide while cooling. The product wasextracted with dichloromethane. The extract was washed with water,dried, filtered and evaporated. The residue was solidified in a mixtureof 2,2'-oxybispropane and a few drops of acetonitrile. The solid productwas filtered off and crystallized from acetonitrile. After cooling to 0°C., the product was filtered off and dried in vacuo at 40° C., yielding1.9 parts (42.8%) ofcis-4-(acetylamino)-5-chloro-2-methoxy-N-[3-methoxy-1-[4-oxo-4-(1-pyrrolidinyl)butyl]-4-piperidinyl]benzamidehemihydrate; mp. 149.7° C. (compound 114).

Pharmacological Examples

The useful gastrointestinal motility stimulating properties of thecompounds of the present invention and their capability to acceleratethe gastric emptying can be demonstrated in the following tests.

Example 29: Amplification of Contractions Induced by SubmaximalTransmural Stimulation of the Guinea-Pig Ileum

Non-terminal ileum segments of the guinea-pig were vertically suspendedwith a preload of 1 g in a 100 ml tyrode bath (37.5° C.) and gassed witha mixture of 95% O₂ and 5% CO₂. Contractions were measuredisometrically. Transmural excitation was applied over the whole lengthof the ileum strip by means of two platinum electrodes (0.5 mmdiamater), the anode was passed through the lumen of the ileum, thecathode was dipped in the bath solution. The tissue was excited withsingle rectangular stimuli of 1 msec duration and submaximal intensityat a frequency of 6 per minute, said stimuli being known to releaseacetylcholine from intramural nerve endings.

After a stabilization period of 30 minutes, a single dose of the testsubstance was added to the bath solution and its effect was followed foranother 30 minutes. Drug effects were expressed as percentage of theinitial contractility value before drug administration. Table 1illustrates the lowest effective concentration of the test substancewhereby a 20% increase was noted over the initial contractility beforedrug administration.

Reference: The Journal of Pharmacology and Experimental Therapeutics,234, 775-783 (1985)

                  TABLE 1                                                         ______________________________________                                                     Lowest effective                                                 Comp. No.    concentration in mg/l                                            ______________________________________                                        80           0.00063                                                          24           0.01                                                             81           0.01                                                             83           0.00063                                                          101          0.01                                                             23           0.01                                                             48           0.00063                                                          50           0.01                                                              3           0.01                                                             90           0.01                                                             27           0.01                                                             51           0.00063                                                          52           0.01                                                             53           0.00063                                                          28           0.01                                                             29           0.01                                                             47           0.01                                                             54           0.01                                                             89           0.01                                                             91           0.01                                                             55           0.00063                                                          56           0.01                                                             109          0.01                                                             57           0.01                                                              4           0.01                                                             61           0.00063                                                           1           0.00063                                                          59           0.01                                                             112          0.01                                                              6           0.00063                                                          64           0.01                                                             84           0.01                                                             39           0.01                                                             40           0.00063                                                          ______________________________________                                    

Example 30: Amplification of Contractions Induced by SupramaximalTransmural Stimulation of the Guinea-Pig Ileum

Non-terminal ileum segments of the guinea-pig were vertically suspendedwith a preload of 1 g in a 100 ml tyrode bath (37.5° C.) and gassed witha mixture of 95% O₂ and 5% CO₂. Contractions were measuredisometrically. Transmural excitation was applied over the whole lengthof the ileum strip by means of two platinum electrodes (0.5 mmdiamater), the anode was passed through the lumen of the ileum, thecathode was dipped in the bath solution. The tissue was excited withsingle rectangular stimuli of 1 msec duration and supramaximal intensity(maximal intensity +20 mA) at a frequency of 6 per minute. After astabilization period of 30 minutes a single dose of the test compoundwas administered to the bath solution resulting in an end concentrationof 0.01 mg/l. Five minutes later another dose was added to a total endconcentration of 0.16 mg/ml. Drug effects were expressed as percentageof the initial contractility value before drug administration. Table 2shows the percentage increase over the initial contractility at aconcentration of 0.01 mg/l and 0.16 mg/l.

                  TABLE 2                                                         ______________________________________                                        Percentage increase over the initial contractility                            Comp.          dosage                                                         No.            0.01 mg/l                                                                              0.16 mg/l                                             ______________________________________                                        48             3.7      22.0                                                  50             3.3      20.3                                                  52             4.3      12.3                                                  53             8.3      22.0                                                  47             4.7      13.7                                                  54             7.0      15.0                                                  91             5.5      14.0                                                  56             5.0      10.7                                                  61             3.3      21.0                                                   1             3.7      20.6                                                  112            5.3      16.7                                                  63             3.0      13.3                                                  64             4.7      35.3                                                  ______________________________________                                    

Example 31: Gastric Emptying of a Liquid Meal in Rats

Gastric emptying was measured in rats according to a modified version ofa method originally devised by Reynell and Spray (J. Physiol. 131:452-456, 1956). Rats were food deprived during 24 hours and isolated inindividual cages. Water was withdrawn at the start of the experiments.The test meal, which consisted of a warm suspension of 200 mg phenol redin 40 ml distilled water was given by oral intubation (0.4 ml/rat) halfan hour after subcutaneous administration of 0.16, 0.63, 2.5, 10 or 40mg/kg of a compound of formula (I) or saline. The stomach was thenexposed by laparotomy, quickly ligated at the pylorus and cardia, andremoved. The stomach was cut up, and its contents was extracted with100ml of 0.1N sodium hydroxide. The phenol red content of this extractwas assayed colorimetrically at 558 nm in a spectrophotometer. A meanvalue of 1.41 extinction units was obtained in saline-treated animals.Table 3 shows the mean extinction units following test injections of0.16, 0.63, 2.5, 10 or 40 mg/kg test compound.

                  TABLE 3                                                         ______________________________________                                        Mean extinction units                                                         Dosage                                                                        Comp.  0.16      0.63    2.5     10    40                                     No.    mg/kg     mg/kg   mg/kg   mg/kg mg/kg                                  ______________________________________                                        87     1.10      0.59    0.47    0.26  0.45                                   82     0.78      0.63    0.43    0.57  --                                      3     186       0.51    0.42    0.34  --                                     90     0.92      0.65    0.53    0.64  0.94                                   47     1.17      0.64    0.78    0.66  --                                     96     1.20      0.58    0.26    0.43  --                                      1     0.87      0.63    0.43    0.45  0.90                                   62     --        0.59    0.66    0.94  0.82                                    5     1.09      0.65    0.18    0.19  0.64                                    7     1.13      --      0.22    0.38  0.36                                   31     0.91      --      0.50    0.40  0.59                                   64     0.74      0.50    0.32    0.46  --                                     17     0.86      0.53    0.42    0.31  0.26                                   19     0.86      0.27    0.31    0.47  0.58                                   44     0.64      0.70    0.35    0.41  0.90                                   65     0.93      0.46    0.23    0.31  --                                     ______________________________________                                    

D. Composition Examples

The following formulations exemplify typical pharmaceutical compositionsin dosage unit form suitable for systemic administration to animal andhuman subjects in accordance with the present invention. "Activeingredient" (A.I.) as used throughout these examples relates to acompound of formula (I), a N-oxide form, a pharmaceutically acceptableacid addition salt or a stereochemically isomeric form thereof.

Example 32: Oral Drops 500 g of the A.I. was dissolved in 0.5 l of2-hydroxypropanoic acid and 1.5 l of the polyethylene glycol at 60°˜80°C. After cooling to 30°˜40° C. there were added 35l of polyethyleneglycol and the mixture was stirred well. Then there was added a solutionof 1750 g of sodium saccharin in 2.5l of purified water and whilestirring there were added 2.5l of cocoa flavor and polyethylene glycolq.s. to a volume of 50 l, providing an oral drop solution comprising0.01 g of the A.I. per ml. The resulting solution was filled intosuitable containers. Example 33: Oral Solution

9 g of methyl 4-hydroxybenzoate and 1 part of propyl 4-hydroxybenzoatewere dissolved in 4 l of boiling purified water. In 3 l of this solutionwere dissolved first 10 g of 2,3-dihydroxybutanedioic acid andthereafter 20 g of the A.I. The latter solution was combined with theremaining part of the former solution and 12 l 1,2,3-propanetriol and 3l of sorbitol 70% solution were added thereto. 40 g of sodium saccharinwere dissolved in 0.5 l of water and 2 ml of raspberry and 2 ml ofgooseberry essence were added. The latter solution was combined with theformer, water was added q.s. to a volume of 20 l providing an oralsolution comprising 0.005 g of the A.I. per teaspoonful (5 ml). Theresulting solution was filled in suitable containers.

Example 34: Capsules 20 g of the A.I., 6 g sodium lauryl sulfate, 56 gstarch, 56 g lactose, 0.8 g colloidal silicon dioxide, and 1.2 gmagnesium stearate were vigorously stirred together. The resultingmixture was subsequently filled into 1000 suitable hardened gelatincapsules, each comprising 0.02 g of the A.I. Example 35: Film-CoatedTablets Preparation of tablet core

A mixture of 100 g of the A.I., 570 g lactose and 200 g starch was mixedwell and thereafter humidified with a solution of 5 g sodium dodecylsulfate and 10 g polyvinylpyrrolidone (Kollidon-K 90 ®) in about 200 mlof water. The wet powder mixture was sieved, dried and sieved again.Then there was added 100 g microcrystalline cellulose (Avicel ®) and 15g hydrogenated vegetable oil (Sterotex ®). The whole was mixed well andcompressed into tablets, giving 10.000 tablets, each comprising 0.01 gof the active ingredient.

Coating

To a solution of 10 g methyl cellulose (Methocel 60 HG ®) in 75 ml ofdenaturated ethanol there was added a solution of 5 g of ethyl cellulose(Ethocel 22 cps ®) in 150 ml of dichloromethane. Then there were added75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g ofpolyethylene glycol was molten and dissolved in 75 ml ofdichloromethane. The latter solution was added to the former and thenthere were added 2.5 g of magnesium octadecanoate, 5 g ofpolyvinylpyrrolidone and 30 ml of concentrated color suspension(Opaspray K-1-2109 ®) and the whole was homogenated. The tablet coreswere coated with the thus obtained mixture in a coating apparatus.

Example 36: Injectable Solution

1.8 g methyl 4-hydroxybenzoate and 0.2 g propyl 4-hydroxybenzoate weredissolved in about 0.5 l of boiling water for injection. After coolingto about 50° C. there were added while stirring 4 g lactic acid, 0.05 gpropylene glycol and 4 g of the A.I. The solution was cooled to roomtemperature and supplemented with water for injection q.s. ad 1 lvolume, giving a solution of 0.004 g A.I. per ml. The solution wassterilized by filtration (U.S.P. XVII p. 811) and filled in sterilecontainers.

Example 37: Suppositories

3 g A.I. was dissolved in a solution of 3 g 2,3-dihydroxybutanedioicacid in 25 ml polyethylene glycol 400. 12 G surfactant (SPAN ®) andtriglycerides (Witepsol 555 ®) q.s. ad 300 g were molten together. Thelatter mixture was mixed well with the former solution. The thusobtained mixture was poured into moulds at a temperature of 37°˜38° C.to form 100 suppositories each containing 0.03 g of the activeingredient.

We claim:
 1. A compound of the formula: ##STR65## an N-oxide form, apharmaceutically acceptable acid addition salt, or a stereoisomeric formthereof, wherein:R¹ is hydrogen, C₁₋₆ alkyl, aryloxycarbonyl, mono- ordi(C₁₋₆ alkyl)aminocarbonyl, pyrrolidinylcarbonyl, orpiperidinylcarbonyl; R² is hydrogen; R³, R⁴, and R⁵ each independentlyare hydrogen, C₁₋₆ alkyloxy, halo, nitro, amino, mono- or di(C₁₋₆alkyl)amino, C₁₋₆ alkylcarbonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, or C₁₋₆ alkylsulfonyl; R⁶ is hydrogen, hydroxy, C₁₋₆alkyl, C₁₋₆ alkyloxy, halo, or amino; and L is a radical of the formula:##STR66## wherein Alk is C₁₋₄ alkanediyl; Y¹ is NR⁷ wherein R⁷ ishydrogen or C₁₋₄ alkyl; and R⁸ and R⁹ each independently are C₁₋₄ alkyl;

    R.sup.13 --(CO)--O--Alk--                                  (d)

wherein Alk is C₁₋₄ alkanediyl; and R¹³ is C₁₋₄ alkyl, C₃₋₆ cycloalkyl,or aryl; or

    R.sup.14 --(CO)--Y.sup.1 --Alk--                           (e)

wherein Alk is C₁₋₄ alkanediyl; Y¹ is NR⁷ wherein R⁷ is hydrogen or C₁₋₄alkyl; and R¹⁴ is arylC₁₋₆ alkyl wherein the C₁₋₆ alkyl moiety issubstituted with hydroxy or C₁₋₆ alkylcarbonyloxy, wherein aryl isphenyl optionally substituted with 1, 2, or 3 substituents eachindependently selected from halo, hydroxy, C₁₋₄ alkyl, and C₁₋₄alkyloxy.
 2. A compound according to claim 1 wherein the substituents onthe 3- and the 4- position of the piperidine ring have the cisconfiguration.
 3. A chemical compound according to claim 2 wherein thebenzamide part is substituted on the meta position with R³ being chloro,bromo, C₁₋₄ alkylaminosulfonyl, aminosulfonyl or C₁₋₄ alkylsulfonyl, onthe para position with R⁴ being amino and on the ortho position with R⁵being hydroxy or C₁₋₄ alkyloxy.
 4. The compound of claim 1 wherein thecompound iscis-4-amino-5-chloro-N-[1-[2-[(dibutylamino)carbonylamino]ethyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide.5. The compound of claim 1 wherein the compound iscis-N-[2-[4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy-1-piperidinyl]ethyl]-α-(hydroxymethyl)benzeneacetamide.6. A pharmaceutical composition comprising one or more inert carriersand as active ingredient a gastrointestinal motility stimulating amountof a compound as claimed in claim
 1. 7. A pharmaceutical compositionaccording to claim 6 wherein the substituents on the 3- and the 4-position of the piperidine ring have the cis configuration.
 8. Apharmaceutical composition according to claim 7 wherein the benzamidepart is substituted on the meta position with R³ being chloro, bromo,C₁₋₄ alkylaminosulfonyl, aminosulfonyl or C₁₋₄ alkylsulfonyl, on thepara position with R⁴ being amino and on the ortho position with R⁵being hydroxy or C₁₋₄ alkyloxy.
 9. A method of treating warm-bloodedanimals suffering from motility disorders of the gastrointestinalsystem, which method comprises the systemic administration to saidwarm-blooded animals of an effective gastrointestinal stimulating amountof a compound as claimed in claim
 1. 10. A method according to claim 9wherein the substituents on the 3- and the 4- position of the piperidinering have the cis configuration.
 11. A method according to claim 10wherein the benzamide part is substituted on the meta position with R³being chloro, bromo, C₁₋₄ alkylaminosulfonyl, aminosulfonyl or C₁₋₄alkylsulfonyl, on the para position with R⁴ being amino and on the orthoposition with R⁵ being hydroxy or C₁₋₄ alkyloxy.